ABSTRACT Tobacco smoking remains a major public health concern globally. Although there are FDA-approved therapeutic options available, they are far from adequate to maintain long-term smoking abstinence in most smokers. Thus, discovering novel efficacious pharmacotherapies to aid in smoking cessation remains an urgent clinical need. Nicotine, the major component in tobacco that is responsible for tobacco addiction, stimulates the mesolimbic dopaminergic system via activating nicotinic acetylcholine receptors (nAChRs). Nicotine replacement therapy and the nAChR partial agonist varenicline have achieved limited clinical success by directly modulating the central nAChRs. Indirect modulation of dopaminergic system by non-dopaminergic mechanism may also be able to modulate the addiction-related effects of nicotine. Trace amine associated receptor 1 (TAAR 1) has emerged as a novel target for the development of potential pharmacotherapy to treat drug addiction. In particular, the neuronal distribution of TAAR 1 overlaps with many key regions of the reward pathway, and biochemical studies reveal robust interactions between TAAR 1 signaling and dopamine transporters and D2 receptors. TAAR 1 agonists have been shown to attenuate several addiction-related behavioral effects of cocaine and methamphetamine. However, it is unknown of the role of TAAR 1 in mediating nicotine addiction. We recently observed that a selective TAAR 1 partial agonist, RO5263397, markedly attenuates nicotine induced behavioral sensitization and the discriminative stimulus effects of nicotine. The objective of the present application is to examine the hypothesis that TAAR 1 is a novel drug target for the treatment of nicotine addiction. This hypothesis will be tested by pursuing two specific aims: 1) examine the effects of TAAR 1 full agonist RO5166017 and partial agonist RO5263397 on nicotine self- administration using both fixed ratio and progressive ratio schedules of reinforcement (Aim 1); 2) examine the effects of RO5166017 and RO5263397 on nicotine-associated cue- and nicotine prime-induced reinstatement of extinguished nicotine-seeking behavior (Aim 2). Collectively, the proposed studies systematically evaluate the effects of TAAR 1 agonists on the addiction-related (e.g., reinforcing and reinstatement) effects of nicotine. These data will provide valuable information on the role of TAAR 1 in mediating nicotine addiction. In addition, data obtained in the proposed investigation may contribute to the identification of novel TAAR 1-based pharmacotherapy for smoking cessation.